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Circulation. 1997;95:2471-2472

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(Circulation. 1997;95:2471.)
© 1997 American Heart Association, Inc.

Articles

Is Hepatocyte Growth Factor a Protein With Cardioprotective Activity in the Ischemic Heart?

Wolfgang Schaper, MD, PhD; Thomas Kubin, PhD

the Max-Planck-Institute, Department of Experimental Cardiology, Bad Nauheim, Germany.

Correspondence to Wolfgang Schaper, MD, PhD, Max-Planck-Institute, Department of Experimental Cardiology, Benekestr 2, D-61231 Bad Nauheim, Germany.


Key Words: Editorials • hepatocyte growth factor • myocardial infarction • ischemia

During the past 15 years, hepatocyte growth factor (HGF) and its receptor have been the subject of immense research efforts. The activity of HGF was first demonstrated in the serum of normal and partially hepatectomized rats by Strain et al1 and Michalopoulos et al2 in 1982. During the years 1984 to 1988, Gohda et al3 , Nakamura et al,4 Russell et al,5 and Thaler and Michalopoulos6 independently isolated and purified HGF from different sources, including platelets and serum (the history of the discovery, purification cloning, and functions of HGF are excellently reviewed by Gohda et al7 and Matsumoto and Nakamura.8 ). At that time, HGF was regarded as a growth factor specific to hepatocytes, and most researchers focused mainly on the growth of cultured hepatocytes and liver regeneration. By 1990 or 1991, the importance of HGF entered a new dimension when it was shown that HGF was identical to the scatter factor (SF),9 the fibroblast-derived tumor cytotoxic factor (F-TCF),10 and a fibroblast-derived epithelial morphogen.11 Around the same time, the HGF receptor was identified as the c-met proto-oncogene product.12 13 It became clear that HGF/SF/F-TCF is a multipotent growth factor whose receptor is not only expressed in the normal epithelium of almost every tissue but also in different cell types such as melanocytes, endothelial cells, microglial cells, neurons, hemopoietic cells, and a variety of tumor cell lines of various origins that are also targets of this growth factor.8 The general activities of HGF were found to be mitogenesis, motogenesis (enhancement of cell motility8 ), morphogenesis, promotion of cell survival, tumor inhibition, and homopoiesis.14 In 1993, it was demonstrated that SF/HGF exhibits angiogenic activities in vivo,15 suggesting an important function during ischemic damage. Furthermore, HGF may participate in a cytokine network that regulates tumor invasion and metastasis.16

In this issue of Circulation,17 Ono and colleagues from the University of Kyoto describe the upregulation of HGF and its receptor in a model of myocardial infarction and reperfusion in the rat. This original study shows that although the concentration of blood-borne HGF increases rapidly after reperfusion and remains increased for >24 hours, its receptor is only upregulated in the endothelium of the ischemic reperfused tissue. The authors speculate, with good reason, that the HGF/Met system plays a significant role in angiogenesis and collateral vessel growth. They also point out that our knowledge of the signals that give rise to the production of HGF in other tissues in response to myocardial ischemia is incomplete. It may be part of a defense mechanism that occurs with acute myocardial infarction, analogous to the actions of interleukins. Surprisingly, Ono et al17 show an upregulation of HGF during the trauma of surgery, and this seems to be similar to the increase of insulin-like growth factor 2 that also occurs under these conditions.18 It would be extremely interesting and important to study the HGF/Met system under conditions of true angiogenesis and vasculogenesis in the heart. The authors have made a good start with their infarction study, which hints at the possibility that HGF has a survival and proliferative function for the endothelium, especially under the conditions of infarction in which many, but not all, capillaries perish.

The delayed upregulation (1 day after reperfusion) of HGF in the ischemic region raises the question of the origin of the initial signal because HGF plasma levels were already detected by enzyme-linked immunosorbent assay within 1 hour after reperfusion. Posttranslational control may contribute to this phenomenon, but the rapid expression in other tissues implies that nondamaged tissues also participate in the early release of this cytokine. Ono et al17 show that the HGF message is induced at sites distant from the damaging stimulus, whereas its receptor mRNA is selectively upregulated in the reperfused myocardium. In the heart, immunostaining of myocytes was negative for HGF, whereas fractions of nonmyocytes, especially macrophages and vascular endothelial cells, were positive for HGF. The fact that endothelial cells were also positive for the receptor of HGF and that they were located close to serum growth factors and probably to HGF-secreting macrophages invites speculation that the cardiac endothelium serves as the primary cardiac target of HGF. Although HGF had been considered to be primarily an endocrine-paracrine factor, an autocrine mechanism of the HGF/Met system was found in cases of human lung carcinoma19 and murine NIH 3T3 cells ectopically induced with c-met.20 Taking into account that HGF has the potency to stimulate 2.5-fold the expression of its own receptor after 24 hours in cultured rat hepatocytes (our unpublished observation), it is feasible that the rapid increase in HGF plasma levels initiates the expression of HGF and its receptor in endothelial cells, which results in an autocrine loop. The recruitment of macrophages in the ischemic tissue probably enhances this loop.

This is not the end of the HGF/Met story; it has been suggested that a certain biological signal of HGF is transduced through a receptor distinct from c-met. The responsiveness of T cells to HGF was clearly demonstrated by showing the inducing effects on T-cell adhesion to fibronectin. However, the HGF receptor, c-met, was not shown to be expressed on T cells by any methods used at the protein or mRNA level.21 The responsiveness of T lymphocytes to HGF by a presumably different receptor suggests that as a source of endothelial cell angiogenic mitogens such as vascular endothelial growth factor and basic fibroblast growth factor, they could regulate endothelial functions in part under certain hypoxic conditions.

The study also nicely demonstrates that first, it pays to look beyond the borders of one's own narrow discipline and second, the "baptizing" of growth factors can be very deceptive. HGF has many more targets than the hepatocyte, as is beautifully demonstrated in this study by Ono et al, much like the misnamed fibroblast growth factor, which is not restricted to fibroblasts but is a broad-band mitogen. In addition, vascular endothelial growth factor acts not only as an angiogenic protein but also like an immediate early gene in a variety of stress reactions, and still other growth factors may exert more and different effects than their names would suggest. Although HGF is not well known in the field of cardiovascular research, it is a well-known growth factor that has been the subject of more than 800 research papers during the last 10 years, more than the intensely popular vascular endothelial growth factor with {approx}600 papers during the same period.

The report of Ono and colleagues has raised many interesting questions that will stimulate new research for which they have laid the basis.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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